Cannabinoids are a specific class of psychoactive compounds present in Indian cannabis (Cannabis sativa), including about sixty different molecules, the most representative being cannabinol, cannabidiol and several isomers of tetrahydrocannabinol. Knowledge of the therapeutic activity of cannabis dates back to the ancient dynasties of China, where, 5,000 years ago, cannabis was used for the treatment of asthma, migraine and some gynaecological disorders. These uses later became so established that, around 1850, cannabis extracts were included in the US Pharmacopaeia and remained there until 1947.
Cannabinoids are known to cause different effects on various systems and/or organs, the most important being on the central nervous system and on the cardiovascular system. These effects include alterations in memory and cognition, euphoria, and sedation. Cannabinoids also increase heart rate and vary systemic arterial pressure. Peripheral effects, such as bronchial dilation, immunomodulation, and downregulation of inflammation have also been observed. The capability of cannabinoids to reduce intraocular pressure and to affect respiratory and endocrine systems is also well documented. See e.g. L. E. Hollister, Health Aspects of Cannabis, Pharmacological Reviews, Vol. 38, pp. 1-20, (1986). More recently, it was found that cannabinoids suppress the cellular and humoral immune responses and exhibit antiinflammatory properties. Wirth et al., Antiinflammatory Properties of Cannabichrome, Life Science, Vol. 26, pp. 1991-1995, (1980).
In spite of the foregoing benefits, the therapeutic use of cannabis is controversial, due to its psychoactive effects. Although work in this field has been ongoing since the 1940's, evidence indicating that the peripheral effects of cannabinoids are directly mediated, and not secondary to a CNS effect, has been limited by the lack of receptor characterization, the lack of information concerning an endogenous cannabinoid ligand and, until recently, the lack of receptor subtype selective compounds.
The first cannabinoid receptor was found to be mainly localized in the brain, and, only to a lesser extent, in peripheral tissues. In view of its mRNA localization, it was designated the central receptor ("CB1"). See Matsuda et al., "Structure of a Cannabinoid Receptor and Functional Expression of the Cloned cDNA," Nature, Vol. 346, pp. 561-564 (1990. The second cannabinoid receptor ("CB2") was localized primarily to the spleen with low expression in the CNS, and was postulated to modulate the non psychoactive effects of the cannabinoids. See Munro et el., "Molecular Characterization of a Peripheral Receptor for Cannabinoids," Nature, Vol. 365, pp. 61-65 (1993).
The foregoing indications and the preferential localization of the CB2 receptor in the immune system suggest a specific role of CB2 in modulating the immune and antiinflammatory response of cannabinoids.
The role of CB2 in immunomodulation, inflammation, osteoporosis, cardiovascular, renal and other disease conditions is currently under examination. In light of the fact that cannabinoids act on receptors capable of modulating different functional effects, and in view of the low homology between CB2 and CB 1, the importance of developing a class of drugs selective for the CB2 receptor subtype is evident. The natural or synthetic cannabinoids currently available do not fulfill this function because they are active on both receptor subtypes.
Based on the foregoing, there is a need for compounds which are capable of selectively activating the peripheral cannabinoid receptor. Thus, CB2 agonists offer a unique approach toward the pharmacotherapy of immune disorders, inflammation, osteoporosis, renal ischemia and other pathophysiological conditions.
Recently, some compounds have been prepared and reported capable of acting as agonists on both cannabinoid receptors. For example, use of derivatives of dihydroxypyrrole-(1,2,3-d,e)-1,4-benzoxazine in the treatment of glaucoma and the use of derivatives of 1,5-diphenyl-pyrazole as immunomodultors or psychotropic agents in the treatment of various neuropathologies, migraine, epilepsy, glaucoma, etc are known. See U.S. Pat. No. 5,112,820 and EP 576357, respectively. However, because these compounds are active on both the CB1 and CB2 receptor, they can lead to serious psychoactive effects. Also recently described are indole derivatives which are reported to selectively bind to CB2 over CB1 receptors. See Michel Gallant et al, Bioorganic & Medicinal Chemistry Letters, 6(19), pp. 2263-2268 (1996).